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Abstract: Synthetic biology has recently emerged as an attempt to study biological systems by construction rather than through observation. Work in the field has demonstrated that synthetic gene networks with a specific function can be designed and constructed experimentally and is expected to lead to important application in bioremediation, biosensing, clean fuel and drug bioproduction, and therapeutics. However, designing biological systems that work as expected remains a challenge. Mathematical modeling is often used to guide the design efforts in synthetic biology but the types of models arc often complex and cannot be easily analyzed. In addition, only simple specifications such as the existence of equilibria, limit cycles, or invariance sets are usually considered. In contrast, methods for proving (or disproving) the correctness of software programs and digital circuits have been developed in the field of formal verification. Such systems can be modeled as simple finite transition graphs and algorithms for automatically deciding whether a model satisfies a specification, expressed in temporal logic, are available. Temporal logics are rich enough to capture properties of biological systems relevant to synthetic biology. However, only simple, unrealistic models are directly amenable to formal verification. In this work, we bridge the gap and develop a theoretical framework and a set of computational tools allowing the analysis of realistic models from rich temporal logic specifications. We consider discrete time, piece-wise affine (PWA) systems, which evolve along different affine dynamics in different regions of the continuous state space. This structure results in models that are globally complex and can approximate nonlinear systems with arbitrary accuracy, but are also locally simple, which allows us to construct finite abstractions. Based on this, we develop formal methods for the analysis, parameter synthesis and control of PWA systems from temporal logic specifications.We apply our methods to analyze the synthetic gene networks that can be constructed from a set of available parts. We demonstrate how our tools can identify device designs that fail to meet the required specifications. Such an approach can be used to filter flawed designs before they are implemented experimentally, thereby decreasing the time and cost involved in synthetic biology projects.
This book develops a rational design and systematic approach to construct a gene network with desired behaviors. In order to achieve this goal, the registry of standard biological parts and experimental techniques are introduced at first. Then these biological components are characterized by a standard modeling method and collected in the component libraries, which can be efficiently reused in engineering synthetic gene networks. Based on the system theory, some design specifications are provided to engineer the synthetic gene networks to robustly track the desired trajectory by employing the component libraries.
Many potential applications of synthetic and systems biology are relevant to the challenges associated with the detection, surveillance, and responses to emerging and re-emerging infectious diseases. On March 14 and 15, 2011, the Institute of Medicine's (IOM's) Forum on Microbial Threats convened a public workshop in Washington, DC, to explore the current state of the science of synthetic biology, including its dependency on systems biology; discussed the different approaches that scientists are taking to engineer, or reengineer, biological systems; and discussed how the tools and approaches of synthetic and systems biology were being applied to mitigate the risks associated with emerging infectious diseases. The Science and Applications of Synthetic and Systems Biology is organized into sections as a topic-by-topic distillation of the presentations and discussions that took place at the workshop. Its purpose is to present information from relevant experience, to delineate a range of pivotal issues and their respective challenges, and to offer differing perspectives on the topic as discussed and described by the workshop participants. This report also includes a collection of individually authored papers and commentary.
This book shows how to design and build synthetic gene networks in different host backgrounds. Coverage includes concepts for devising synthetic gene networks and application of mathematical models to the predictable engineering of desired network features.
Synthetic gene networks have evolved from simple proof-of-concept circuits to complex therapy-oriented networks over the past fifteen years. This advancement has greatly facilitated expansion of the emerging field of synthetic biology. Multistability is a mechanism that cells use to achieve a discrete number of mutually exclusive states in response to environmental inputs. However, complex contextual connections of gene regulatory networks in natural settings often impede the experimental establishment of the function and dynamics of each specific gene network. In this work, diverse synthetic gene networks are rationally designed and constructed using well-characterized biological components to approach the cell fate determination and state transition dynamics in multistable systems. Results show that unimodality and bimodality and trimodality can be achieved through manipulation of the signal and promoter crosstalk in quorum-sensing systems, which enables bacterial cells to communicate with each other. Moreover, a synthetic quadrastable circuit is also built and experimentally demonstrated to have four stable steady states. Experiments, guided by mathematical modeling predictions, reveal that sequential inductions generate distinct cell fates by changing the landscape in sequence and hence navigating cells to different final states. Circuit function depends on the specific protein expression levels in the circuit. We then establish a protein expression predictor taking into account adjacent transcriptional regions' features through construction of 120 synthetic gene circuits (operons) in Escherichia coli. The predictor's utility is further demonstrated in evaluating genes' relative expression levels in construction of logic gates and tuning gene expressions and nonlinear dynamics of bistable gene networks. These combined results illustrate applications of synthetic gene networks to understand the cell fate determination and state transition dynamics in multistable systems. A protein-expression predictor is also developed to evaluate and tune circuit dynamics.
This volume provides clear and direct protocols to implement automated Design-Build-Test-Learn (DBTL) into synthetic biology research. Chapters detail techniques to model and simulate biological systems, redesign biological systems, setting up of an automated biolaboratory, step-by-step guide on how to perform computer aided design, RNA sequencing, microfluidics -using bacterial cell free extracts, live mammalian cells, computational and experimental procedures, metabolic burden, computational techniques to predict such burden from models, and how DNA parts can be engineered in mammalian cells to sense, and respond to, and intracellular signals in general. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and cutting-edge, Synthetic Gene Circuits: Methods and Protocols aims to ensure successful results in the further study of this vital field.
Scientific advances over the past several decades have accelerated the ability to engineer existing organisms and to potentially create novel ones not found in nature. Synthetic biology, which collectively refers to concepts, approaches, and tools that enable the modification or creation of biological organisms, is being pursued overwhelmingly for beneficial purposes ranging from reducing the burden of disease to improving agricultural yields to remediating pollution. Although the contributions synthetic biology can make in these and other areas hold great promise, it is also possible to imagine malicious uses that could threaten U.S. citizens and military personnel. Making informed decisions about how to address such concerns requires a realistic assessment of the capabilities that could be misused. Biodefense in the Age of Synthetic Biology explores and envisions potential misuses of synthetic biology. This report develops a framework to guide an assessment of the security concerns related to advances in synthetic biology, assesses the levels of concern warranted for such advances, and identifies options that could help mitigate those concerns.
This book develops a rational design and systematic approach to construct a gene network with desired behaviors. In order to achieve this goal, the registry of standard biological parts and experimental techniques are introduced at first. Then these biological components are characterized by a standard modeling method and collected in the component libraries, which can be efficiently reused in engineering synthetic gene networks. Based on the system theory, some design specifications are provided to engineer the synthetic gene networks to robustly track the desired trajectory by employing the component libraries.